Abstract
Hepatitis C virus (HCV) non-structural protein 3 (NS3) has been shown to affect cellular functions and is thought to contribute to the development of HCV-related hepatocarcinogenesis. In this study, we delineated part of the mechanisms whereby NS3 protein stimulates cell growth in liver (HepG2) and non-liver (HeLa) cells. The expression of NS3 protein enhanced cell growth, c-jun NH(2)-terminal kinase (JNK) activation, DNA binding activities of the transcription factors AP-1 and ATF-2, and c-jun expression, but not the activation of extracellular signal-regulated kinase (ERK) or p38(MAPK). Whereas co-expression of NS3 with its cofactor NS4A inhibited NS3-mediated cell growth without to influence NS3-mediated JNK activation, or to affect the basal activities of ERK or p38(MAPK). Pre-treatment of NS3 protein-expressing cells with JNK inhibitor, SP600125, abolished activation of AP-1 and ATF-2 and inhibited c-jun expression and induced cell growth, suggesting that JNK activation is essential for the stimulation of NS3-mediated cell growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Anthracenes / pharmacology
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Base Sequence
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Cell Division / drug effects
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Cell Line
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Cyclic AMP Response Element-Binding Protein / metabolism
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DNA, Viral / genetics
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression / drug effects
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Genes, Viral / drug effects
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HeLa Cells
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Hepacivirus / drug effects
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Hepacivirus / genetics
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Hepacivirus / pathogenicity*
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism*
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MAP Kinase Signaling System / drug effects
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Tetracycline / pharmacology
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / physiology*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Anthracenes
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Cyclic AMP Response Element-Binding Protein
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DNA, Viral
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Enzyme Inhibitors
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NS3 protein, hepatitis C virus
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NS4 protein, hepatitis C virus
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Transcription Factor AP-1
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Transcription Factors
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Viral Nonstructural Proteins
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pyrazolanthrone
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Tetracycline